A phase I trial of PR-104, a nitrogen mustard prodrug activated by both hypoxia and aldo-keto reductase 1C3, in patients with solid tumors
| Autor: | Mark D. Pegram, Danny Rischin, John Gutheil, William A. Denny, Michael B. Jameson, Adam V. Patterson, William R. Wilson |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Male Cancer Research Neutropenia Metabolic Clearance Rate Nitrogen Mustard Compound Pharmacology Reductase Toxicology chemistry.chemical_compound Pharmacokinetics Multienzyme Complexes Neoplasms Humans Medicine Prodrugs Pharmacology (medical) Hypoxia Infusions Intravenous Fatigue Aged Aldo-keto reductase Molecular Structure business.industry Anemia Middle Aged Hypoxia (medical) Prodrug Nitrogen mustard Treatment Outcome Oncology Biochemistry chemistry Area Under Curve Nitrogen Mustard Compounds Toxicity Female medicine.symptom business |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 65:791-801 |
| ISSN: | 1432-0843 0344-5704 |
| Popis: | PR-104 is a "pre-prodrug" designed to be activated to a dinitrobenzamide nitrogen mustard cytotoxin by nitroreduction in hypoxic regions of tumors. This study was conducted to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetics (PK) of PR-104 in patients with advanced solid tumors.Patients with solid tumors refractory or not amenable to conventional treatment were evaluated in a dose-escalation trial of PR-104 administered as a 1-h intravenous (IV) infusion every 3 weeks. The plasma PK of PR-104 and its primary metabolite, PR-104A, were evaluated.Twenty-seven patients received a median of two cycles of PR-104 in doses ranging from 135 to 1,400 mg/m(2). The MTD of PR-104 as a single-dose infusion every 3 weeks was established as 1,100 mg/m(2). One of six patients treated at 1,100 mg/m(2) experienced DLT of grade 3 fatigue. Above the MTD, the DLTs at 1,400 mg/m(2) were febrile neutropenia and infection with normal absolute neutrophil count. No objective responses were observed, although reductions in tumor size were observed in patients treated at dosesor = 550 mg/m(2). The plasma PK of PR-104 demonstrated rapid conversion to PR-104A, with approximately dose-linear PK of both species.PR-104 was well tolerated at a dose of 1,100 mg/m(2) administered as an IV infusion every 3 weeks. The area under the PR-104A plasma concentration-time curve at this dose exceeded that required for activity in human tumor cell cultures and xenograft models. The recommended dose of PR-104 as a single agent for phase II trials is 1,100 mg/m(2) and further trials are underway. |
| Databáze: | OpenAIRE |
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